Optimal intertemporal curative drug expenses: The case of hepatitis C in France.

We study intertemporal tradeoffs that health authorities face when considering the control of an epidemic using innovative curative medical treatments. We set up a dynamically controlled susceptible-infected-recovered (SIR) model for an epidemic in which patients can be asymptomatic, and we analyze the optimality conditions of the sequence of cure expenses decided by health authorities at the onset of the drug innovation process. We show that analytical conclusions are ambiguous because of their dependence on parameter values. As an application, we focus on the case study of hepatitis C, the treatment for which underwent a major upheaval when curative drugs were introduced in 2014. We calibrate our controlled SIR model using French data and simulate optimal policies. We show that the optimal policy entails some front loading of the intertemporal budget. The analysis demonstrates how beneficial intertemporal budgeting can be compared to non-forward-looking constant budget allocation.

Echocardiographic Parameters Associated With Cardiorespiratory Fitness and Physical Activity in Childhood Acute Lymphoblastic Leukemia Survivors.

BACKGROUND: Children's exposure to chemotherapeutic agents causes several long-term adverse effects but physical activity has been evidenced to be an effective strategy to improve cardiac function. This cross-sectional study aimed to explore the association between physical activity levels, cardiorespiratory fitness, and cardiac parameters measured by echocardiography. METHODS: Participants were 216n childhood acute lymphoblastic leukemia survivors who underwent a maximal cardiopulmonary exercise test and self-reported their daily minutes of moderate to vigorous physical activity. They underwent a complete transthoracic echocardiographic assessment. Systolic and diastolic function analysis and strain images analysis were performed. The associations were studied through the preventive fraction (examined with univariate crude and adjusted logistic regression models) of regular physical activity (≥150 min·wk-1) and adequate cardiorespiratory fitness levels (above the median ≥ 32.0 mL·kg-1·min-1) on cardiac parameters. RESULTS: Crude analysis shows that regular physical activity was associated with a significant preventive fraction in mitral E/A ratio (56%; P = .013), while adjusted analyses highlighted a nonsignificant reduction of 74% to 37% in the prevalence of cardiac parameters associated with physical activity. Similar associations of adequate cardiorespiratory fitness on cardiac parameters were observed. Adjusted analyses revealed a nonsignificant reduction of 7% to 86% in the prevalence of cardiac parameters associated with cardiorespiratory fitness. CONCLUSION: This study reports that regular physical activity and adequate cardiorespiratory fitness were associated with a higher preventive fraction. Thus, engaging in physical activity prevents childhood acute lymphoblastic leukemia survivors' cardiac dysfunctions. These findings are novel and clinically relevant in pediatric cardiooncology and provide additional evidence to strengthen the benefits of exercise as long-term care in childhood cancer survivors.

Cardiorespiratory Fitness and Cardiac Magnetic Resonance Imaging in Childhood Acute Lymphoblastic Leukemia Survivors.

BACKGROUND: Childhood acute lymphoblastic leukemia survivors' anthracycline-induced cardiotoxicity could be prevented with good cardiorespiratory fitness levels and regular physical activity. This cross-sectional study aimed to assess the association between cardiorespiratory fitness and physical activity with cardiac magnetic resonance parameters. METHODS: A total of 96 childhood acute lymphoblastic leukemia survivors underwent a maximal cardiopulmonary exercise test and answered physical activity questionnaires. We calculated the odds ratio of the preventive fraction of regular physical activity (≥150 min/wk) and adequate cardiorespiratory fitness levels (above the median ≥31.4 mL·kg-1·min-1) on cardiac magnetic resonance parameters (left ventricular [LV] and right ventricular [RV] morphological and functional parameters). RESULTS: An adequate cardiorespiratory fitness was associated with a significant preventive fraction for LV (up to 84% for LV end-diastolic volume) and RV volumes (up to 88% for RV end-systolic volume). The adjusted analyses highlighted a preventive fraction of 36% to 91% between an adequate cardiorespiratory fitness and LV and RV parameters, late gadolinium enhancement fibrosis, and cardiac magnetic resonance relaxation times. No associations were reported with regular physical activity. CONCLUSIONS: This study provides additional evidence regarding the benefits of an adequate cardiorespiratory fitness level for childhood cancer survivors' cardiac health.

Identifying the effects of scientific information and recommendations on physicians' prescribing behavior.

We investigate how the prescribing behavior of physicians reacts to scientific information and recommendations released by public authorities. Taking the example of antidepressant drugs, we use French panel data on exhaustive prescriptions made by a representative sample of general practitioners to more than 110,000 depressed patients between 2000 and 2008. New results revealing an increase in suicidal thinking among children taking selective serotonin reuptake inhibitors (SSRIs) were reported in 2004 and prompted the release of new guidelines by public health authorities. We identify the effect of this unexpected warning on physicians' drug choices while addressing the possibility that patients heterogeneity may be correlated with unobserved physician characteristics. While the warning decreased the average probability of prescribing SSRIs, we find that physicians' responses to the warning were very heterogeneous and larger if the physician had a higher preference for prescribing SSRIs before the warning.

Optimizing Initial Intrathecal Drug Ratio for Refractory Cancer-Related Pain for Early Pain Relief. A Retrospective Monocentric Study.

OBJECTIVE: Intrathecal (IT) drug delivery has shown its efficiency in treating refractory cancer pain, but switching opioids from the systemic to the intrathecal route is a challenging phase. Moreover, associations are widely used and recommended. Few data deal with the initial dosage of each drug. Analyzing conversion factors and initial dosages used in intrathecal therapy seems essential to decreasing the length of titration and to delivering quick pain relief to patients. METHODS: We retrospectively analyzed data from consecutive adult patients implanted with an intrathecal device for cancer pain and treated at the Institut de Cancérologie de l'Ouest, in Angers, France, for four years. The main goal was to identify factors associated with early pain relief after intrathecal drug delivery system (IDDS) implantation. RESULTS: Of the 220 IDDS-treated patients, 70 (32%) experienced early pain relief (EaPR) and 150 (68%) delayed pain relief (DePR). Performance Status stage and initial IT ropivacaine:IT morphine ratio were the variables independently associated with EaPR. The best IT ropivacaine:IT morphine ratio to predict EaPR was 5:1, with a 73% (95% confidence interval [CI] = 64.8% to 79.6%) sensitivity and a 67.1% (95% CI = 54.9% to 77.9%) specificity. EaPR subjects experienced better pain relief (-84% vs -60% from baseline pain score, P < 0.0001), shorter length of hospitalization (7 vs 10 days, P < 0.0001), and longer survival (155 vs 82 days, P = 0.004). CONCLUSIONS: Local anesthetic:morphine ratio should be considered when starting IDDS treatment. EaPR during the IT analgesia titration phase was associated with better pain relief and outcomes in patients with refractory cancer-related pain.

Prolonged perioperative thoracic epidural analgesia may improve survival after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: A comparative study.

OBJECTIVE: To assess the effectiveness of prolonged perioperative thoracic epidural analgesia (PEA) on long term survival of patients who underwent a complete cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal peritoneal metastases (CPM). BACKGROUND: Grade III-IV morbidity affects long term outcomes after CRS and HIPEC. As compared with opioid administered via patient-controlled analgesia (PCA), PEA reduces morbidity. METHOD: From 2005 to 2016, 150 patients underwent CRS plus HIPEC with or without prolonged PEA. Clinical data and outcomes collected from prospective database were analyzed. Survival was assessed in terms of analgesic method using Kaplan-Meier plots and a propensity score. RESULTS: Patients 'characteristics of 59 patients in PCA group were comparable to those of 91 patients in PEA group, except for age, ASA score and fluid requirements, significantly more important in PEA group. Grade III-IV morbidity was 62.7% in PCA group compared with 36.3% in PEA group (p = 0.0015). Median overall survival (OS) of PEA group was 54.7 months compared to 39.5 months in PCA group (p = 0.0078). When adjusted on the covariates, using the propensity score, the PEA significantly improves OS [HR 0.40 (95% CI: 0.28-0.56)] (p < 0.0001) and disease free survival (DFS) [HR 0.61 (95% CI: 0.45-0.81] (p < 0.0007) CONCLUSIONS: In this retrospective study of patients who underwent a complete CRS and HIPEC for colorectal peritoneal metastases, the perioperative thoracic epidural analgesia prolonged for over 72 h reduced significantly the grade III-IV morbidity and may improve OS and DFS.

Intrathecal Drug Delivery Systems for Refractory Pancreatic Cancer Pain: Observational Follow-up Study Over an 11-Year Period in a Comprehensive Cancer Center.

BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer-related death in Europe and the United States. Studies have demonstrated that patients with pancreatic cancer have a high prevalence of pain, with rates varying from 47% to 82%. Analgesia using intrathecal drug delivery systems (IDDS) has been poorly studied specifically in this population. METHODS: The IDDS for pancreatic cancer pain was a follow-up observational study designed to evaluate 11-year results of IDDS for refractory pancreatic cancer pain at the Institut de Cancérologie de L'Ouest, Paul Papin in France. Patients were followed from March 2006 to April 2017. Patients were selected for IDDS based on multidisciplinary meeting discussion. All IDDS-treated patients were prescribed a combined intrathecal analgesics regimen through a catheter placed according to painful metameric level. Postimplant assessment of pain was determined using a numerical rating scale (NRS). Patients were followed via day-hospital visits and telephone calls at least monthly until death. Pain scores were compared using the Wilcoxon signed rank test. Overall survival (OS) was estimated using the Kaplan-Meier method and compared between groups by log rank tests. RESULTS: Ninety-three patients received IDDS, and total therapy duration accounts for 10,300 IDDS days. Implanted patients suffered from severe pain before implantation (median presurgical NRS, 8 [interquartile range, 7-9]) despite a median 360 mg (260-600) oral morphine equivalent daily dose. Median OS in the whole cohort after intrathecal treatment start was 82 days (95% confidence interval, 59-95). Median OS after surgery for implantable pump was 91 days (83-111) and for external pump 27 days (20-49; P < .0001). IDDS was associated with pain relief with a significant statistical difference between preimplantation NRS pain score and 1 week (median, -6 [-7 to -4]; P < .001), 1 month (median, -5 [-6 to -3]; P < .001), and 3 months (median, -6 [-7 to -4]; P < .001). Severe pain (NRS score, ≥7) decreased from 89.2% before surgery to 4.5% after 1 week, 6.7% after 1 month, and 10.3% after 3 months of IDDS implant (P < .01). Global complications rate was low, consistent with published literature. CONCLUSIONS: Despite our study's limitations, results suggest that long-term IDDS for refractory malignant pain due to pancreatic cancer was both efficacious and safe in pancreatic cancer pain. We have demonstrated, in the largest series of IDDS for pancreatic cancer pain reported yet, a clinically and statistically significant pain reduction in patients receiving IDDS.

Patient satisfaction and acceptance of their totally implanted central venous catheter: a French prospective multicenter study.

INTRODUCTION: Most cancer patients require a totally implanted central venous catheter (TIVAD) for their treatment. In a previous study, we developed and validated a questionnaire dubbed QASICC (Questionnaire for Acceptance of, and Satisfaction with, Implanted Central Venous Catheter) assessing patient satisfaction with, and acceptance of, their TIVAD. In the present study, we conducted a large, prospective, multicenter study in cancer patients aimed to analyze factors that could influence patients' acceptance of, and satisfaction with, their device. METHODS: The QASICC is composed of 22 items assessing 5 dimensions. The construction and validation of the questionnaire was achieved using validated methodology to determine its psychometric characteristics. The questionnaire was submitted to 720 patients in 11 French institutions; 567 answers were analyzed. RESULTS: Younger patients had the most difficulties in coping with their TIVAD, especially regarding daily activities and their body image and private life compared to older patients. Sex was significantly related to patient satisfaction, with worse scores in women. Breast tumor location was also correlated with low TIVAD acceptance. TIVAD on the right side also positively influenced satisfaction and acceptance of the device. CONCLUSIONS: QASICC has proved to be efficient, and to detect known issues regarding daily activities and body image. As our population was mostly composed of women with breast cancer, our results reflect specific aspects of this population. The TIVAD remains generally well-accepted and our questionnaire should help health-care workers to better address the specific needs of their patients based on the answers provided.

Rationale for Prospective Assays of Intrathecal Mixtures Including Morphine, Ropivacaine and Ziconotide: Prevention of Adverse Events and Feasibility in Clinical Practice.

BACKGROUND: Use of intrathecal admixtures is widespread, but compounding these is sometimes challenging and may result in errors and complications causing super-potency or sub potency adverse events in patients or malfunctions in the pump itself. OBJECTIVE: The purpose of this study is to evaluate the accuracy of compounding of intrathecal admixtures through a prospective, systematic quantitative analysis of each component of the mixture before delivery to patients. STUDY DESIGN: Observational follow up prospective study of intrathecal mixtures components concentrations before refills. SETTINGS: Assays were performed on all intrathecal admixtures produced by the ICO-Paul Papin compounding pharmacy between January 2013 and October 2014 using Ultra High Performance Liquid Chromatography (U.H.P.L.C.). In addition, pH levels of admixtures have been measured since June 2014. When measured concentrations were 15% above or below the required concentrations, the mixture was excluded and compounded again. RESULTS: 1729 mixtures were analyzed. Mean deviation from theoretical values was -1.17% ± 0.28% for morphine, -0.95% ± 1.07% for ropivacaine, and 4.82% ± 0.6% for ziconotide. Exclusion rates were 8.33% overall, but fell from 11.67% in 2013 to 4.97% in 2014. Most exclusions were caused by inaccuracy in the dose of ziconotide. Average mixture pH of the 603 tested admixtures was 4.83 ± 0.6%. LIMITATIONS: This study is monocentric and limitations include also its non-randomized nature with no clinical comparison of the rate of adverse events with a refill process without control of each component concentrations. CONCLUSION: Prospective assays provide benefits in ensuring accuracy of intrathecal mixture compounding and in preventing overdosing or sub dosing, most notably concerning Ziconotide.

[Multicenter validation study of a questionnaire assessing patient satisfaction with and acceptance of totally-implanted central venous access devices]. / Validation multicentrique d'un questionnaire évaluant l'acceptation et la satisfaction des patients porteurs de chambre à cathéter implantable : le questionnaire QASICC.

OBJECTIVE: Most cancer patients require a totally-implanted central venous access device (TIVAD) for their treatment. This was a prospective, multicenter, open study to: (i) develop and validate a French-language questionnaire dubbed QASICC (Questionnaire for Acceptance of and Satisfaction with Implanted Central Venous Catheter) assessing patient's satisfaction with and acceptance of their TIVAD; (ii) develop a mean score of patient's acceptance and satisfaction; (iii) look for correlation between QASICC score and TIVAD patient/tumor pathology/device characteristics. METHODS: From 2011 November to 2012 December, the first version of the QASICC questionnaire that included 27 questions assessing seven dimensions was re-tested among 998 cancer patients in eleven French cancer hospitals (eight cancer research institutes and three university/general hospitals). The goal was: (i) to reduce the questionnaire item and dimension number (pertinency, saturation effect, item correlation); (ii) to assess its psychometric properties, demonstrate its validity and independency compared to (EORTC) QLQC30; (iii) to correlate clinical and pathological patient's/tumor's/TIVAD's parameters with the QASICC questionnaire score (the higher the overall score, the greater the acceptance and satisfaction). The questionnaire was administered to the patient 30 days (±15 days) after TIVAD's implantation. RESULTS: Among 998 questionnaires given to cancer patients, 658 were analyzed and 464 were fully assessed as there was no missing data. Time to fill-in the questionnaire was five minutes in 90% patients. Final QASICC tool included twenty-two questions assessing four homogeneous dimensions (65%

SERS spectroscopic approach to study doxorubicin complexes with Fe(2+) ions and drug release from SPION-based nanocarriers.

The aim of this work is to present a surface-enhanced Raman scattering (SERS) spectroscopic approach to study complexes of a frequently used antineoplastic agent, doxorubicin (DOX), with ferrous ions, at sub-micromolar concentrations in aqueous solution. The SERS bands of DOX were assigned according to critical analysis of literature. Prior to the complexation study, the spectral changes related to the drug orientation on the silver surface and to its protonation state were highlighted. The SERS spectra of DOX-Fe(2+) complexes showed several features distinguishing them from the free drug, protonated or not on the phenolic part of its chromophore. The lowest detectable content of the DOX-iron complex in the presence of free DOX was estimated to be 5-10%. This property is particularly interesting from the analytical point of view, since it allows for study of drug-iron interactions upon the drug loading on and release from magnetic drug carriers based on superparamagnetic iron oxide nanoparticles (SPIONs), stabilized with citrate ions or coated with polyethylene glycol (PEG) polymer. Our SERS data indicate that the drug loaded on magnetic nanocarriers as DOX-iron chelate was mainly released in the free DOX form. These results demonstrate the strength of the SERS approach for the study of DOX-iron interactions in relation to delivery issues and drug action mechanisms.

A double-blind randomized trial of wound and intercostal space infiltration with ropivacaine during breast cancer surgery: effects on chronic postoperative pain.

BACKGROUND: The efficacy of local anesthetic wound infiltration for the treatment of acute and chronic postoperative pain is controversial and there are no detailed studies. The primary objective of this study was to evaluate the influence of ropivacaine wound infiltration on chronic pain after breast surgery. METHODS: In this prospective, randomized, double-blind, parallel-group, placebo-controlled study, 236 patients scheduled for breast cancer surgery were randomized (1:1) to receive ropivacaine or placebo infiltration of the wound, the second and third intercostal spaces and the humeral insertion of major pectoralis. Acute pain, analgesic consumption, nausea and vomiting were assessed every 30 min for 2 h in the postanesthesia care unit and every 6 h for 48 h. Chronic pain was evaluated 3 months, 6 months, and 1 yr after surgery by the brief pain inventory, hospital anxiety and depression, and neuropathic pain questionnaires. RESULTS: Ropivacaine wound infiltration significantly decreased immediate postoperative pain for the first 90 min, but did not decrease chronic pain at 3 months (primary endpoint), or at 6 and 12 months postoperatively. At 3 months, the incidence of chronic pain was 33% and 27% (P = 0.37) in the ropivacaine and placebo groups, respectively. During follow-up, brief pain inventory, neuropathic pain, and anxiety increased over time in both groups (P < 0.001) while depression remained stable. No complications occurred. CONCLUSION: This multicenter, prospective study shows that ropivacaine wound infiltration after breast cancer surgery decreased immediate postoperative pain but did not decrease chronic pain at 3, 6, and 12 months postoperatively.

Magnetic nanocarriers of doxorubicin coated with poly(ethylene glycol) and folic acid: relation between coating structure, surface properties, colloidal stability, and cancer cell targeting.

We report the efficient one-step synthesis and detailed physicochemical evaluation of novel biocompatible nanosystems useful for cancer therapeutics and diagnostics (theranostics). These systems are the superparamagnetic iron oxide nanoparticles (SPIONs) carrying the anticancer drug doxorubicin and coated with the covalently bonded biocompatible polymer poly(ethylene glycol) (PEG), native and modified with the biological cancer targeting ligand folic acid (PEG-FA). These multifunctional nanoparticles (SPION-DOX-PEG-FA) are designed to rationally combine multilevel mechanisms of cancer cell targeting (magnetic and biological), bimodal cancer cell imaging (by means of MRI and fluorescence), and bimodal cancer treatment (by targeted drug delivery and by hyperthermia effect). Nevertheless, for these concepts to work together, the choice of ingredients and particle structure are critically important. Therefore, in the present work, a detailed physicochemical characterization of the organic coating of the hybrid nanoparticles is performed by several surface-specific instrumental methods, including surface-enhanced Raman scattering (SERS) spectroscopy, X-ray photoelectron spectrometry (XPS), and time-of-flight secondary ion mass spectrometry (ToF-SIMS). We demonstrate that the anticancer drug doxorubicin is attached to the iron oxide surface and buried under the polymer layers, while folic acid is located on the extreme surface of the organic coating. Interestingly, the moderate presence of folic acid on the particle surface does not increase the particle surface potential, while it is sufficient to increase the particle uptake by MCF-7 cancer cells. All of these original results contribute to the better understanding of the structure-activity relationship for hybrid biocompatible nanosystems and are encouraging for the applications in cancer theranostics.

Poly(ethylene glycol)-stabilized silver nanoparticles for bioanalytical applications of SERS spectroscopy.

The present work depicts the efficient one-step synthesis and detailed evaluation of stable aqueous colloids of silver nanoparticles (NPs) coated with poly(ethylene glycol) (PEG) covalently attached to their surface. Due to steric repulsion between polymer-modified surfaces, the stability of the nanoparticle suspension was preserved even at high ionic strength (0.1 M NaCl). At the same time, the PEG coating remains sufficiently permeable to allow surface-enhanced Raman scattering (SERS) from micromolar concentrations of small molecules such as the anticancer drug mitoxantrone (MTX). The enhancement efficiency of the hot spot-free Ag-PEG was compared to that of citrate-stabilized Ag colloids used after pre-aggregation. The potential of the polymer-stabilized colloids developed in this study is discussed in terms of bioanalytical applications of SERS spectroscopy.

Intracellular applications of analytical SERS spectroscopy and multispectral imaging.

The aim of this tutorial review is to give an overview of the state of the art of intracellular applications of analytical SERS spectroscopy. We pay particular attention to nanoparticle-based SERS spectroscopy since this currently dominates the published literature on non-disturbing analysis of live cells. We describe recent advances in this domain due to the development of multispectral imaging and to the combined use of SERRS (surface-enhanced resonance Raman scattering) and fluorescence spectroscopy. Finally, a perspective view is given on the tip-based approaches like tip-enhanced Raman spectroscopy (TERS) which allow micrometric and nanometric resolution.

On the interaction of doxorubicin with oleate ions: fluorescence spectroscopy and liquid-liquid extraction study.

Increase of lipophilicity of cationic doxorubicin (DOX) by its association with a fatty acid ion is of interest for pharmaceutical formulations and could have an impact on the drug delivery into cancer cells. On the basis of spectroscopic analysis of intrinsic DOX fluorescence, this study provides an experimental evidence of DOX-oleate interactions as function of ion/drug molar ratio (R) and pH. An electrostatic attraction to oleates is dominant for the cationic form of DOX (pH 6.5) and a hydrophobic interaction is characteristic of the molecular form of DOX (pH 8.6). A high content of sodium oleate vesicles ([oleate]>/=0.2 mM, R>/=20) limits the electrostatic and hydrophobic interactions at pH 6.5 while favoring the hydrophobic interactions at pH 8.6. The influence of these interactions on the lipophilicity of the cationic form of DOX is analyzed by measuring the apparent partition coefficient (aqueous buffer pH 6.5/methylene chloride). The results show a lipophilicity gain for the cationic form of DOX in presence of 10 : 1 ion/drug molar ratio, while no lipophilicity increase is observed at 50 : 1 molar ratio.

Differential subcellular distribution of mitoxantrone in relation to chemosensitization in two human breast cancer cell lines.

The present work investigates the relationship between cancer cell chemosensitivity and subcellular distribution, molecular interaction, and metabolism of an anticancer drug. To get insights into this relationship, we took advantage of the differential sensitivity of two breast cancer cell lines, MDA-MB-231 and MCF-7, to anthracyclines, along with the property of docosahexaenoic acid (DHA, 22:6n-3), to differentially enhance their cytotoxic activity. The fluorescent drug mitoxantrone (MTX) was used because of the possibility to study its subcellular accumulation by confocal spectral imaging (CSI). The use of CSI allowed us to obtain semiquantitative maps of four intracellular species: nuclear MTX bound to DNA, MTX oxidative metabolite in endoplasmic reticulum, cytosolic MTX, and finally, MTX in a low polarity environment characteristic of membranes. MDA-MB-231 cells were found to be more sensitive to MTX (IC50 = 18 nM) than MCF-7 cells (IC50 = 196 nM). According to fluorescence levels, the nuclear and cytosolic MTX content was higher in MCF-7 than in MDA-MB-231 cells, indicating that mechanisms other than nuclear MTX accumulation account for chemosensitivity. In the cytosol, the relative proportion of oxidized MTX was higher in MDA-MB-231 (60%) than in MCF-7 (7%) cells. DHA sensitized MDA-MB-231 (approximately 4-fold) but not MCF-7 cells to MTX and increased MTX accumulation by 1.5-fold in MDA-MB-231 cells only. The DHA-stimulated accumulation of MTX was attributed mainly to the oxidative metabolite. Antioxidant N-acetyl-L-cysteine inhibited the DHA effect on both metabolite accumulation and cell sensitization to MTX. We conclude that drug metabolism and compartmentalization are associated with cell chemosensitization, and the related cytotoxicity mechanisms may involve oxidative stress.

Optimization of iron oxide nanoparticles encapsulation within poly(d,l-lactide-co-glycolide) sub-micron particles.

This work describes a method for preparation of sub-micron poly(d,l-lactide-co-glycolide) (PLGA) particles loaded with magnetite/maghemite nanoparticles to be used as magnetically-controlled drug delivery systems. The methodology of simple emulsion/evaporation technique has been optimized to provide greater iron oxide loading rates. The surface of iron oxide nanoparticles was coated with oleic acid (OA) for better compatibility with organic phase containing the polymer. To increase their loading into polymeric sub-micron particles, we added dried iron oxide nanoparticles in variable ferrite/polymer ratio of 1:1; 1:1.5 and 1:2 w/w. Composition and surface properties of obtained composite sub-micron particles have been studied in comparison with those of ferrite-free PLGA sub-micron particles. Presence of magnetite/maghemite was qualitatively confirmed by characteristic bands in the FT-IR spectra of composite sub-micron particles. Quantification of the incorporated iron was achieved by AAS. The highest incorporation rates of ferrite (up to 13.5% w/w) were observed with initial ferrite/polymer ratio of 1:1 w/w. TEM images indicate that the composite sub-micron particles are nearly spherical. According to laser granulometry data, average hydrodynamic diameter of the composite sub-micron particles is close to 280nm, independently of ferrite presence. Electrophoretic properties (zeta potential) were very similar for both composite and ferrite-free PLGA sub-micron particles, thus indicating that the polymeric coating should mask the surface of ferrite nanoparticles buried inside. Finally, composite sub-micron particles exhibit superparamagnetic property.

Nanovectors for anticancer agents based on superparamagnetic iron oxide nanoparticles.

During the last decade, the application of nanotechnologies for anticancer drug delivery has been extensively explored, hoping to improve the efficacy and to reduce side effects of chemotherapy. The present review is dedicated to a certain kind of anticancer drug nanovectors developed to target tumors with the help of an external magnetic field. More particularly, this work treats anticancer drug nanoformulations based on superparamagnetic iron oxide nanoparticles coated with biocompatible polymers. The major purpose is to focus on the specific requirements and technological difficulties related to controlled delivery of antitumoral agents. We attempt to state the problem and its possible perspectives by considering the three major constituents of the magnetic therapeutic vectors: iron oxide nanoparticles, polymeric coating and anticancer drug.

Conformational modifications of alpha gliadin and globulin proteins upon complex coacervates formation with gum Arabic as studied by Raman microspectroscopy.

As a molecular model of gelatin-free coacervates, complexes of pea globulin and alpha gliadin proteins with gum arabic prepared at different acidic pH values are studied using Raman microspectrometry. Raman spectra confirm higher content of beta-sheets and random coils in pea globulin and dominating alpha-helical structures in alpha gliadin. For protein-gum arabic complexes, Raman data support the existence of specific pH conditions for optimal complex coacervation (pH 2.75 for globulin and pH 3.0 for gliadin(1)), when (i) pH-induced conformational perturbations of free protein structure are the strongest and (ii) compensation of these perturbations by gum arabic is the most pronounced. Conformations implied in the protein-gum complexes are mainly beta-sheets in pea globulin and alpha-helix in alpha gliadin. The role of electrostatic and non-Coulombic interactions (intermolecular hydrogen bonds) in stabilizing of protein-polysaccharide complexes is discussed in relation with the overall structure and the charge density profile of these two proteins.